tbuckley/cabot-search huggingface dataset:
Fractional Flow Reserve or Intravascular Ultrasonography to Guide PCI
Authors: Bon-Kwon Koo, Xinyang Hu, Jeehoon Kang, Jinlong Zhang, Jun Jiang, Joo-Yong Hahn, Chang-Wook Nam, Joon-Hyung Doh, Bong-Ki Lee, Weon Kim, Jinyu Huang, Fan Jiang, Hao Zhou, Peng Chen, Lijiang Tang, Wenbing Jiang, Xiaomin Chen, Wenming He, Sung-Gyun Ahn, Myeong-Ho Yoon, Ung Kim, Joo-Myung Lee, Doyeon Hwang, You-Jeong Ki, Eun-Seok Shin, Hyo-Soo Kim, Seung-Jea Tahk, Jian’an Wang
Journal: New England Journal of Medicine (2022)

In patients with coronary artery disease who are being evaluated for percutaneous coronary intervention (PCI), procedures can be guided by fractional flow reserve (FFR) or intravascular ultrasonography (IVUS) for decision making regarding revascularization and stent implantation. However, the differences in clinical outcomes when only one method is used for both purposes are unclear.We randomly assigned 1682 patients who were being evaluated for PCI for the treatment of intermediate stenosis (40 to 70% occlusion by visual estimation on coronary angiography) in a 1:1 ratio to undergo either an FFR-guided or IVUS-guided procedure. FFR or IVUS was to be used to determine whether to perform PCI and to assess PCI success. In the FFR group, PCI was to be performed if the FFR was 0.80 or less. In the IVUS group, the criteria for PCI were a minimal lumen area measuring either 3 mm2 or less or measuring 3 to 4 mm2 with a plaque burden of more than 70%. The primary outcome was a composite of death, myocardial infarction, or revascularization at 24 months after randomization. We tested the noninferiority of the FFR group as compared with the IVUS group (noninferiority margin, 2.5 percentage points).The frequency of PCI was 44.4% among patients in the FFR group and 65.3% among those in the IVUS group. At 24 months, a primary-outcome event had occurred in 8.1% of the patients in the FFR group and in 8.5% of those in the IVUS group (absolute difference, -0.4 percentage points; upper boundary of the one-sided 97.5% confidence interval, 2.2 percentage points; P = 0.01 for noninferiority). Patient-reported outcomes as reported on the Seattle Angina Questionnaire were similar in the two groups.In patients with intermediate stenosis who were being evaluated for PCI, FFR guidance was noninferior to IVUS guidance with respect to the composite primary outcome of death, myocardial infarction, or revascularization at 24 months. (Funded by Boston Scientific; FLAVOUR ClinicalTrials.gov number, NCT02673424.).
Dolutegravir in Pregnancy as Compared with Current HIV Regimens in the United States
Authors: Kunjal Patel, Yanling Huo, Jennifer Jao, Kathleen M. Powis, Paige L. Williams, Deborah Kacanek, Lynn M. Yee, Ellen G. Chadwick, Stephanie Shiau, Denise L. Jacobson, Sean S. Brummel, Leila Sultan-Beyer, Christian R. Kahlert, Rebecca Zash, George R. Seage
Journal: New England Journal of Medicine (2022)

Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited.We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results.Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar.Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
Linezolid for Drug-Resistant Tuberculosis
Authors: Guy Thwaites, Nhung V. Nguyen
Journal: New England Journal of Medicine (2022)

The development of a highly effective, oral, 6-month regimen for the treatment of multidrug-resistant tuberculosis, which previously took 18 to 24 months to cure, is one of the defining achievements of the tuberculosis research community in this century. The results of the Nix-TB study, which were published in the Journal in 2020,1 showed that the combination of two new drugs, bedaquiline and pretomanid, with a repurposed oxazolidinone antibiotic agent, linezolid, given for 6 to 9 months to patients with drug-resistant or complicated multidrug-resistant tuberculosis, resulted in a favorable outcome in 98 of 109 patients (90%) at 6 months after the . . .
Choosing a Method for Guiding PCI
Authors: Jane A. Leopold
Journal: New England Journal of Medicine (2022)

In contemporary clinical practice, interventional cardiologists use both fractional flow reserve (FFR) and intravascular ultrasonography (IVUS) to guide percutaneous coronary intervention (PCI) for intermediate coronary stenosis (i.e., a narrowing of the coronary-artery lumen by 40 to 70%). FFR, a physiological test, is used to evaluate the ischemic potential of a stenosis and decide whether PCI is needed. IVUS, a high-resolution intracoronary imaging method, is used to select the appropriate stent size and to determine whether the stent is correctly placed and sized after implantation. These tools are necessary because the severity of a stenosis on a coronary angiogram does not . . .
Telescoping the Diagnostic Process
Authors: Clement D. Lee, Evan Shirey, Brittany Guttadauria, Chén C. Kenyon
Journal: New England Journal of Medicine (2022)

A 3-year-old boy presented with abdominal pain and vomiting. He had associated chills without fever, nonbloody and nonbilious emesis, constipation, reduced urinary output, and a decreased activity level.
Covid-19 Vaccines — Immunity, Variants, Boosters
Authors: Dan H Barouch
Journal: New England Journal of Medicine (2022)

T he coronavirus disease 2019 (Covid-19) pandemic has claimed an estimated 15 million lives, including more than 1 million lives in the United States alone.The rapid development of multiple Covid-19 vaccines has been a triumph of biomedical research, and billions of vaccine doses have been administered worldwide.Challenges facing the Covid-19 vaccine field include inequitable vaccine distribution, vaccine hesitancy, waning immunity, and the emergence of highly transmissible viral variants that partially escape antibodies.This review summarizes the current state of knowledge about immune responses to Covid-19 vaccines and the importance of both humoral and cellular immunity for durable protection against severe disease. A nti v ir a l Immunit yThe immune system is broadly divided into the innate and adaptive immune systems.Innate immune responses are the first line of defense against viruses and are rapidly triggered when cellular pattern-recognition receptors, such as toll-like receptors, recognize pathogen-associated molecular patterns.Innate antiviral immunity includes secretion of type I interferons, antiviral cytokines, and certain cellular responses, including neutrophils, monocytes and macrophages, dendritic cells, and natural killer cells. 1 Adaptive immune responses, the second line of defense against viruses, involve antigen-specific recognition of viral epitopes.Adaptive immunity includes two complementary branches of the immune system: humoral immunity and cellular immunity.Humoral immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) includes antibodies that bind the SARS-CoV-2 spike protein and either neutralize the virus or eliminate it through other effector mechanisms. 2,3ellular immunity to SARS-CoV-2 includes virus-specific B cells and T cells, which provide long-term immunologic memory and rapidly expand on reexposure to antigen.B cells produce antibodies, CD8+ T cells directly eliminate virally infected cells, and CD4+ T cells provide help to support the immune responses.5][6][7] For a highly transmissible SARS-CoV-2 variant that largely escapes neutralizing antibodies, cellular immunity may be particularly important for longterm protection against severe disease.
Letter Regarding “Impact of Immune-Related Adverse Events on Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Hepatocellular Carcinoma”
Authors: Yinhan Wang, Yongfa Huang, Huayu Yang, Yilei Mao
Journal: Liver Cancer (2022)

Immunologic checkpoint inhibitors (ICIs) have demonstrated efficacy in a variety of malignancies. Despite impressive therapeutic benefits, ICIs may induce profound immune-related adverse events (irAEs). While the occurrence of irAEs may implicate improved T cell activity, whether irAEs predicts anti-tumor immune responses remains controversial. The paper by Kennedy Yao Yi Ng et al. adds to the evidence of the impact of irAEs in advanced hepatocellular carcinoma, which demonstrated that multi-system involvement of irAEs positively correlated with treatment responses and survival. We are, however, concerned about the grouping method and potential statistical bias. Therefore, we listed a few questions and possible solutions under each circumstance, which we would like to share with authors and readers.
Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection
Authors: Ivy A. Rosales, Grace K. Mahowald, Kristen Tomaszewski, Kiyohiko Hotta, Naoya Iwahara, Takuya Otsuka, Takahiro Tsuji, Yusuke Takada, Ellen Acheampong, Milagros Araujo-Medina, Amy Bruce, Andrea Rios, Anthony Benedict Cosimi, Nahel Elias, Tatsuo Kawai, Hannah Gilligan, Kassem Safa, Leonardo V. Riella, Nina E. Tolkoff-Rubin, Winfred W. Williams, Rex Neal Smith, Robert B. Colvin
Journal: Journal of the American Society of Nephrology (2022)

To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes.We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes.The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (P=3.4 × 10-5). Random forest analysis correlated 3-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts.Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histologic CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.
HLA-DQ Mismatches Lead to More Unacceptable Antigens, Greater Sensitization, and Increased Disparities in Repeat Transplant Candidates
Authors: Dylan Isaacson, Jesse D. Schold, Michael W. Gmeiner, Hannah C. Copley, Vasilis Kosmoliaptsis, Anat R. Tambur
Journal: Journal of the American Society of Nephrology (2022)

In single-center studies, HLA-DQ mismatches stimulate the most pathogenic donor-specific antibodies. However, because of limitations of transplant registries, this cannot be directly confirmed with registry-based analyses.We evaluated patients in the Scientific Registry of Transplant Recipients who were relisted after renal graft failure with new, unacceptable antigens corresponding to the HLA typing of their previous donor (UA-PD) as a proxy for donor-specific antibodies. Linear regression was applied to estimate the effects of HLA mismatches on UA-PD and the effects of UA-PD on calculated panel reactive antibody (cPRA) values for 4867 kidney recipients from 2010 to 2021.Each additional HLA-DQ mismatch increased the probability of UA-PD by 25.2% among deceased donor transplant recipients and by 28.9% among living donor transplant recipients, significantly more than all other HLA loci (P<0.05). HLA-DQ UA-PD increased cPRA by 29.0% in living donor transplant recipients and by 23.5% in deceased donor transplant recipients, significantly more than all loci except for HLA-A in deceased donor transplant recipients (23.1%). African American deceased donor transplant recipients were significantly more likely than Hispanic and White recipients to develop HLA-DQ UA-PD; among living donor transplant recipients, African American or Hispanic recipients were significantly more likely to do so compared with White recipients. Models evaluating interactions between HLA-DR/DQ mismatches revealed largely independent effects of HLA-DQ mismatches on HLA-DQ UA-PD.HLA-DQ mismatches had the strongest associations with UA-PD, an effect that was greatest in African American and Hispanic recipients. cPRA increases with HLA-DQ UA-PD were equivalent or larger than any other HLA locus. This suggests a need to consider the effects of HLA-DQ in kidney allocation.
Extensive Pulmonary Cyst Formation in Erdheim-Chester Disease
Authors: Shiyao Wang, Jun Li, Yanhong Ren, Min Liu, Bei Wang, Huaping Dai
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Extensive Pulmonary Cyst Formation in Erdheim-Chester Disease." American Journal of Respiratory and Critical Care Medicine, 206(12), pp. 1546–1547
The Selection of Medical Students
Authors: Alan Shepard
Journal: JAMA (1987)

<h3>To the Editor.—</h3> The article by DeVaul et al<sup>1</sup>is an example of a study that becomes so caught up in statistical analysis and impossible comparisons that the authors come to a conclusion that not only does not follow from the data presented, but also displays the frightening realities of how certain admission committees are run. The authors claim that "the traditional interview process probably does not enhance the ability to predict performance of medical school applicants." This conclusion is based on a comparison of applicants initially accepted to medical school with a group of applicants initially rejected. The performance of these students in medical school and one year after graduation revealed no significant differences. "Even when the top 50 students in committee preference were compared with the 50 IR [initially rejected] applicants, there were no differences." We are given a table (Table 3) that compares the two groups
Efficacy and Safety of Rezivertinib (BPI-7711) in Patients With Locally Advanced or Metastatic/Recurrent EGFR T790M-Mutated NSCLC: A Phase 2b Study
Authors: Yuankai Shi, Shiman Wu, Ke Wang, Shundong Cang, Wenxiu Yao, Yun Fan, Lin Wu, Meijuan Huang, Xingya Li, Yueyin Pan, Zhixiong Yang, Bo Zhu, Gongyan Chen, Jianhua Shi, Meili Sun, Jian Fang, Lijun Wang, Zhaohong Chen, Chunling Liu, Jingzhang Li, Jiwei Liu, Shenghua Sun, Yanqiu Zhao, Yanzhen Guo, Zili Meng, Zhefeng Liu, Zhigang Han, Hong Lu, Rui Ma, Sheng Hu, Guofang Zhao, Zheng Liu, Congying Xie, Diansheng Zhong, Hui Zhao, Huiqing Yu, Longzhen Zhang, Minghong Bi, Shanyong Yi, Shuliang Guo, Tienan Yi, Wen Li, Yingcheng Lin, Yongqian Shu, Zhendong Chen, Zhongliang Guo, Michael Greco, Tingting Wang, Haijiao Shen
Journal: Journal of Thoracic Oncology (2022)

IntroductionRezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) targeting both EGFR-sensitizing mutations and EGFR T790M mutation. This study aimed to evaluate the efficacy and safety of rezivertinib in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC.MethodsPatients with locally advanced or metastatic/recurrent NSCLC with confirmed EGFR T790M mutation who progressed after first-/second-generation EGFR TKI therapy or primary EGFR T790M mutation were enrolled. Patients received rezivertinib at 180 mg orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR) assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival, and safety. This study is registered with Clinical Trials.gov (NCT03812809).ResultsA total of 226 patients were enrolled from July 5, 2019, to January 22, 2020. By the data cutoff date on January 24, 2022, the median duration of follow-up was 23.3 months (95% confidence interval [CI]: 22.8–24.0). The ORR by blinded independent central review was 64.6% (95% CI: 58.0%–70.8%), and DCR was 89.8% (95% CI: 85.1%–93.4%). The median duration of response was 12.5 months (95% CI: 10.0–13.9), and median PFS was 12.2 months (95% CI: 9.6–13.9). The median overall survival was 23.9 months (95% CI: 20.0–not calculated [NC]). Among 91 (40.3%) patients with central nervous system (CNS) metastases, the median CNS PFS was 16.6 months (95% CI: 11.1–NC). In 29 patients with more than or equal to one brain target lesion at baseline, the CNS ORR and CNS DCR were 69.0% (95% CI: 49.2%–84.7%) and 100% (95% CI: 88.1%–100%), respectively. Time to progression of CNS was 16.5 months (95% CI: 9.7–NC). Of 226 patients, 188 (83.2%) had at least one treatment-related adverse event, whereas grade more than or equal to 3 occurred in 45 (19.9%) patients. No interstitial lung disease was reported.ConclusionsRezivertinib was found to have promising efficacy and favorable safety profile for patients with locally advanced or metastatic/recurrent NSCLC with EGFR T790M mutation.
The Intrauterine Device and Cervical Neoplasia
Authors: Ralph M. Richart
Journal: JAMA (1967)

The progression rate of cervical dysplasia to carcinoma in situ was calculated in 114 subjects wearing intrauterine contraceptive devices (IUDs) and in 221 subjects not using such a device. The progression rates in these two groups, calculated by the life table method, were not significantly different, suggesting that the IUD exerts no significant carcinogenic effect on the human uterine cervix.
Consultative Geriatric Assessment for Ambulatory Patients
Authors: Arnold M. Epstein
Journal: JAMA (1990)

Previous studies have shown that comprehensive geriatric assessment and follow-up can improve the health of hospitalized elderly patients. To evaluate the effectiveness of consultative geriatric assessment and limited follow-up for ambulatory patients, we randomized 600 elderly patients who were enrolled in a health maintenance organization into three groups: (1) consultation by a geriatric assessment team, (2) consultation by a "second opinion" internist, and (3) only traditional health maintenance organization services (control patients). The geriatric assessment team identified previously unrecognized problems in 35% of patients and advised changes in medication regimens for more than 40%. Nevertheless, patients who received assessment achieved only a small benefit in cognitive function after 3 months, which was not sustained for 1 year. There was no difference among groups in other measures of health status. Consultative geriatric assessment with limited follow-up did not benefit most older ambulatory patients in a health maintenance organization; if such care can be used effectively for ambulatory patients, it will require either additional targeting or continuing care or both. (<i>JAMA</i>. 1990;263:538-544)
Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy
Authors: Nadja Meumann, Marti Cabanes‐Creus, Moritz Ertelt, Renina Gale Navarro, Julie Lucifora, Qinggong Yuan, Karin Nien‐Huber, Ahmed Abdelrahman, Xuan‐Khang Vu, Liang Zhang, Ann‐Christin Franke, Christian Schmithals, Albrecht Piiper, Annabelle Vogt, Maria Gonzalez‐Carmona, Jochen T. Frueh, Evelyn Ullrich, Philip Meuleman, Steven R. Talbot, Margarete Odenthal, Michael Ott, Erhard Seifried, Clara T. Schoeder, Joachim Schwäble, Leszek Lisowski, Hildegard Büning
Journal: Hepatology (2022)

Background and Aims: Current liver‐directed gene therapies look for adeno‐associated virus (AAV) vectors with improved efficacy. With this background, capsid engineering is explored. Whereas shuffled capsid library screenings have resulted in potent liver targeting variants with one first vector in human clinical trials, modifying natural serotypes by peptide insertion has so far been less successful. Here, we now report on two capsid variants, MLIV.K and MLIV.A, both derived from a high‐throughput in vivo AAV peptide display selection screen in mice. Approach and Results: The variants transduce primary murine and human hepatocytes at comparable efficiencies, a valuable feature in clinical development, and show significantly improved liver transduction efficacy, thereby allowing a dose reduction, and outperform parental AAV2 and AAV8 in targeting human hepatocytes in humanized mice. The natural heparan sulfate proteoglycan binding ability is markedly reduced, a feature that correlates with improved hepatocyte transduction. A further property that might contribute to the improved transduction efficacy is the lower capsid melting temperature. Peptide insertion also caused a moderate change in sensitivity to human sera containing anti‐AAV2 neutralizing antibodies, revealing the impact of epitopes located at the basis of the AAV capsid protrusions. Conclusions: In conclusion, MLIV.K and MLIV.A are AAV peptide display variants selected in immunocompetent mice with improved hepatocyte tropism and transduction efficiency. Because these features are maintained across species, MLIV variants provide remarkable potential for translation of therapeutic approaches from mice to men.
Joint Study of Extracranial Arterial Occlusion
Authors: William F. Blaisdell
Journal: JAMA (1969)

Twenty-four centers participated in the Joint Study of Extracranial Arterial Occlusion. There were 2,400 operations carried out between 1961 and 1968 with an overall surgical mortality of 4.5%. The highest complication rate, including mortality, was noted in patients operated on within two weeks of the development of an acute neurological deficit. With improved intraoperative technique and more critical selection of patients, there has been a steady decline in surgical mortality over the past eight years.